concanavalin-a and 2-aminofluorene

Here, we attempt to reveal how 2-aminofluorene (AF), benzo(alpha)pyrene (BP) and their major metabolites affect T-cell responses to antigenic and mitogenic stimuli. P-450-related metabolism of these parent compounds to metabolites seems to precede the observed immunosuppression; therefore, we investigated the influence of alpha-naphthoflavone (P-450 inhibitor) and beta-naphthoflavone (P-450 inducer) on BP and AF immunosuppression. We used proliferative responses to concanavalin A and the allogeneic mixed lymphocyte response as correlates of immunosuppression. We also attempted to correlate DNA-adduction to the extent of observed immunosuppression for AF and BP metabolites. These data show that the pathway to the strongest immunosuppressive agents for polycyclic aromatic hydrocarbons and arylamines are divergent and related to metabolism by P450 enzymes.

Topics: Acetyl Coenzyme A; Animals; Antigens; Benzo(a)pyrene; Benzoflavones; beta-Naphthoflavone; Carcinogens; Cell Proliferation; Cells, Cultured; Concanavalin A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; DNA Adducts; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fluorenes; Immunosuppressive Agents; Interleukin-2; Lymphocyte Culture Test, Mixed; Mice; Mice, Inbred C3H; Mitogens; Spleen; T-Lymphocytes

The ability of the polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BP) and its metabolites to be immunosuppressive has been well documented by many investigators. The arylamine, 2-aminofluorene (AF) and its metabolic intermediates have not been as widely studied in this regard. Here, we investigate the effect of BP, 3-hydroxy-BP (3-OH-BP), AF, N-hydroxy-AF (N-OH-AF) and acetyl-AF (AAF) on T-cell proliferation using the T-cell mitogen, Concanavalin A (ConA). These compounds as well as BP-7, 8-diol-9, 10-epoxide (BPDE) were also used to determine their effect on T-cell-mitogen binding. Both AF and BP are substrates for the P-450 and flavin-containing monooxygenase enzyme system, which can be induced with beta-naphthoflavone (beta NF). We incubated beta nF with BP and AF to determine the effect of a P-450 inducer on BP and AF mediated-ConA suppression. Here we demonstrate that BP, 3-OH-BP, AF, and AAF are able to suppress the proliferative response to ConA, while N-OH-AF cannot. Further, we show that BP, 3-OH-BP, BPDE, AF and N-OH-AF do not alter the ability of ConA to bind the mitogen receptor of splenic T-cells, indicating an intracellular mechanism for suppression. Studies with beta NF indicate that this P-450 inducer enhances the anti-proliferative effect of BP, while it abolishes this effect of AF.

Topics: Animals; Benzo(a)pyrene; Carcinogens; Concanavalin A; Female; Fluorenes; Lymphocyte Activation; Male; Mice; Mice, Inbred C3H; Mitogens; T-Lymphocytes